Protocol for identifying genetic modifiers of phenotypes in individuals with disease-associated variants

The variable expressivity of disease-associated variants suggests a role for secondary variants in modifying the clinical presentation of these primary variants. Here, we present a protocol for identifying associations of secondary variants with phenotypes. We describe steps for prioritizing distinct classes of secondary variants throughout the genome. We then detail statistical procedures for finding associations of secondary variants and phenotypes in individuals carrying disease-associated variants. For complete details on the use and execution of this protocol, please refer to Jensen et al.¹.